Illuminating the chemical biology of stem cell decisions in plant roots

项目摘要 小分子对于多细胞生物体中干细胞行为的适当调节至关重要。 因此，这些化合物的生物合成、感知或代谢的缺陷可导致 发育异常和疾病。尽管小分子至关重要，但绝大多数 我们对它们的功能的理解来自间接测量。通常，小分子的研究 生物学仅限于遗传或生物化学方法，这些方法基于化合物的生物学特性将功能作用归于化合物。 与这些分子相互作用的基因或蛋白质的特性。或者，研究小分子 使用化学分析方法使大块组织均质化并破坏信号的天然环境。 高分辨率空间信息在发育中至关重要，其中干细胞仅占发育的一小部分。 组织。为了更深入地研究干细胞行为的化学调控，我的实验室将申请 能够直接测量小分子在其天然环境中的定位和活性的技术 发展背景。这项工作将使用植物的根来完成，这是一个强大的发育系统。 根将所有的干细胞储存在根尖，这产生了一个可以检查的发育梯度 在一片组织中。我的实验室将利用这种梯度来研究小分子在干细胞中的作用， 决策我们将使用质谱成像和可视化绘制植物根系的发育化学 小分子与蛋白质的相互作用，使用合成的荧光报告。代谢物驱动的发育 通过研究柠檬酸盐和视黄醇（retinaldehyde）（retinaldehyde），两种高度保守的 在根干细胞分裂和身份中具有新作用的代谢物。本研究将产生：1）高空间 分辨率地图集详细说明了干细胞决定的化学概况，从再生到分化2） 对促进应激弹性干细胞亚群增殖的途径的新见解和3） 阐明了调节干细胞模式的动态代谢物驱动的信号传导途径。我们的结果 这表明，有许多小分子具有重要的发展作用，等待发现。进行 在化学和发育生物学交叉领域的研究将为干细胞提供机理性的见解 使用单一学科方法不可能做出的细胞决定。因此，这项工作将丰富 我们对支配干细胞模式形成、维持 分裂和命运的获取。

Project Summary Small molecules are critical for proper regulation of stem cell behavior in multicellular organisms. Consequently, defects in the biosynthesis, perception, or metabolism of these compounds can cause developmental abnormalities and disease. Despite the critical importance of small molecules, the vast majority of our understanding of their functions is derived from indirect measurements. Typically, studies of small molecule biology are limited to genetic or biochemical approaches that ascribe functional roles to compounds based on the properties of the genes or proteins that interact with these molecules. Alternatively, small molecules are studied using chemical analysis approaches that homogenize bulk tissue and destroy the native context of the signals. High-resolution spatial information is critical in development, where stem cells comprise only a small fraction of the tissue. To enable deeper investigations of chemical regulation of stem cell behavior, my lab will apply technologies capable of directly measuring the localization and activity of small molecules in their native developmental contexts. This work will be done using plant roots, which are a powerful developmental system. Roots store all of their stem cells at the root tip, which generates a developmental gradient that can be examined in a single slice of tissue. My lab will leverage this gradient to investigate the role of small molecules in stem cell decisions. We will map the developmental chemistry of plant roots using mass spectrometry imaging and visualize small molecule interactions with proteins using a synthetic fluorogenic reporter. Metabolite-driven developmental mechanisms will be explored in depth by investigating citrate and retinaldehyde (retinal), two highly conserved metabolites with novel roles in root stem cell divisions and identity. This research will generate: 1) high-spatial resolution atlases detailing the chemical profiles of stem cell decisions, from regeneration to differentiation 2) novel insight into pathways that promote proliferation in stress-resilient stem cell subpopulations and 3) elucidation of dynamic metabolite-driven signaling pathways that regulate stem cell patterning. Our results suggest that there are many small molecules with important developmental roles that await discovery. Conducting research at the intersection of chemistry and developmental biology will provide mechanistic insight into stem cell decisions that would not be possible using a single-disciplinary approach. Accordingly, this work will enrich our understanding of the conserved and divergent principles that govern stem cell patterning, maintenance, divisions, and fate acquisition.